The metanephric kidneys originate during the fifth week of gestation in humans, during day 12 of embryonic rat development, and during day 20–28 of embryonic pig development, when outgrowths of the mesonephric ducts, so-called ureteric buds, collect about their distal ends, intermediate mesoderm (metanephric blastema) located caudal to the mesonephros. The outgrowths push radially into the surrounding mass of metanephric blastema and give rise to the collecting ducts of the kidneys. The proximal ends of the ureteric bud give rise to the ureter and renal pelvis. The metanephric blastema differentiates into all of the tubular structures of the adult nephron with the exception of the collecting system. The origin of the glomerular blood vessels, is in part, extrametanephric.
Studies of metanephric organ culture have shown that kidney development in vitro is dependent upon the expression of a number of polypeptides within the developing organ. Blocking the expression or action of any of transforming growth factor alpha (TGF-α), hepatocyte growth factor (HGF), insulin-like growth factor I (IGF I) or insulin-like growth factor II (IGF II), inhibits metanephric growth and development in vitro (Hammerman M R, Seminars in Nephrology (1995) 15:291–299). Vascular endothelial growth factor (VEGF), is also produced by developing kidneys. Blocking VEGF activity in vivo inhibits renal vascularization (Kitamano et al., J. Clin. Invest. 99: (1997) 2351–2357). Exposure of developing metanephroi to vitamin A stimulates glomerulogenesis in vitro (Vilar et al., Kidn. Intl. 49: (1995) 1478–1487).
Once renal development is complete in a mammal, no new nephrons form. The loss of renal functional mass that occurs following insults to the adult kidney is compensated, in the short term, by hypertrophy and hyperfunction of the remaining nephrons. However, these compensatory changes are often transient and under some circumstances maladaptive in that they may lead to further loss of renal function.
End-stage chronic renal failure afflicts more than 250,000 individuals in the United States alone, most of whom are treated using dialysis, a treatment with considerable morbidity. Another treatment is renal allotransplantation, which is limited by the number of available organs for transplantation. A possible solution to the lack of organ availability is the use of renal xenografts. The clinical renal xenografts performed to date have utilized primate donors, because the closer species are phylogenetically, the more easily xenografts are accepted. The clinical experience with the use of primates as kidney donors dates from the 1960s. However, the results of xenografting of kidneys has been unsatisfactory, and this technique has remained an experimental one for three decades.
Another possible solution to the lack of organ availability is the transplantation of developing kidneys (metanephric allografts or xenografts). The allotransplantation of developing metanephroi into adult animals has been attempted by several investigators. Woolf et al., (Kidn. Intl., (1990) 38:991–997) implanted pieces of sectioned metanephroi originating from embryonic mice into the cortex of kidneys of outbred mice. Differentiation and growth of donor nephrons occurred in the host kidney. Glomeruli were vascularized, mature proximal tubules were formed and extensions of metanephric tubules into the renal medulla were observed. Glomerular filtration was demonstrable in donor nephrons. In contrast to the case in newborn mice, metanephric tissue transplanted into adult mice neither grew nor differentiated, but was extruded as a poorly differentiated mass under the renal capsule.
Abrahamson et al. (Lab. Invest (1991) 64:629–639) implanted metanephroi from day 17 rat embryos beneath the renal capsule of adult rat hosts. Within 9–10 days post-implantation, every graft became vascularized, new nephrons were induced to form and glomerular and tubular cytodifferentiation occurred. However, signs of rejection such as hypercellular glomeruli and lymphocytic infiltrates in peritubular spaces were obvious by 10 days post-transplantation.
Robert et al. (Am. J. Physiol. (1996) 271:F744–F753) grafted metanephroi from embryonic day 12 mouse embryos into kidney cortices of adult and newborn mouse hosts. They demonstrated that by 7 days post-transplantation, grafts into both newborn and adult hosts were vascularized by components originating from both donor and host.
Barakat and Harrison (J. Anat., (1971) 110:393–407) transplanted sections of embryonic rat metanephroi into a subcutaneous site in the abdominal wall of closely related or unrelated adult rats. Lymphocytic infiltration of the graft and replacement of the graft by fibrosis occurred in both related and unrelated adult hosts, but was more rapid in the unrelated hosts.
Growth factors have been used for the purpose of reducing transplant rejection and improving transplant function. U.S. Pat. No. 5,135,915 to Czarniecki et al., describes immersing grafts in a formulation comprising transforming growth factor for a period of a few minutes up to several days prior to transplantation. The pretreatment with TGF-β purportedly reduces transplant rejection. U.S. Pat. No. 5,728,676, to Halloran describes the administration of insulin-like growth factor (IGF) before, during, or after organ transplantation for the purpose of inhibiting transplant rejection. In a canine renal autotransplantation model, it was found that storing the removed kidneys in a preservation solution supplemented with IGF-I for a period of 24 hours prior to transplantation back into the dog, significantly improved renal function for the first 5 days following transplantation (Petrinec et al., Surgery (1996) 120(2):221–226).